Transforming growth factor beta (TGF-beta), secreted within an inflammatory site or injected locally, induces leukocyte margination, chemotaxis, and accumulation. In addition to its potent direct chemotactic activity, TGF-beta promotes this leukocyte response by influencing cell surface integrin expression. At picomolar concentrations, TGF-beta increases steady-state mRNA levels for both the alpha5, alpha3, and beta1 molecules on the cell surface. Functionally, TGF-beta promotes, in a dose- and time-dependent fashion, monocyte adhesion to type IV collagen, laminin, and fibronectin. TGF-beta also triggers transcriptional and posttranscriptional regulation of type IV collagenase. Thus, TGF-beta may play a pivotal role in the early phases of inflammation and repair through its ability to mediate monocyte adhesion, chemotaxis, and enzymatic digestion of extracellular matrix, whereas in chronic lesions, excess TGF-beta may contribute to persistent leukocyte accumulation. Therefore, in exploring potential antagonists of TGF-beta, we have identified the Th2-derived cytokine, IL-4, as an endogenous inhibitor of TGF-beta-stimulated monocyte functions including adhesion and collagenase production. Interestingly, TGF-beta-stimulated monocytes expressed elevated levels of IL-4 receptor mRNA and protein, augmenting their susceptibility to the anti-inflammatory effects of IL-4. In additional studies, IL-4 was shown to suppress both TGF-beta and IL- 1beta gene expression induced by TGF-beta. Suppression of IL-1beta by IL-4 occurred subsequent to TGF-beta interaction with its receptor and signalling, and was regulated at the transcriptional level. Coincident with the suppression of IL-1beta, IL-4 augmented TGF-beta-induced IL-1 receptor antagonist (IL-1ra) production, expanding its anti-inflammatory potential. Thus, these data indicate that IL-4 antagonizes the inflammatory actions of TGF-beta on immature monocytes, but works together with TGF-beta to mediate immune suppression by deactivating stimulated monocyte/macrophages and by inducing IL-1ra.